Many aging-related diseases are characterized by protein malfolding, accumulation, and aggregation in the endoplasmic reticulum (ER). This proposal addresses the basis for cellular toxicity of protein malfolding in the ER. The eIF2a kinase PERK coordinates transcription and translational control and promotes cell survival under conditions of ER stress. Humans and mice with mutations in PERK develop Wolcott Rallison syndrome of infantile diabetes mellitus. To identify molecular mechanisms involved in PERK's ability to protect cells from ER stress consequences, Caenorhabditis elegans will serve as a genetic model system to identify mutations that render pek-1 (the orthologue of PERK) essential (a synthetic lethal screen). The diversity of mammalian ER stress response is conserved in this model organism and genetics is a powerful means to address complex physiological processes. This screen will identify genes involved in adaptation and survival during ER stress. The specific aims of this proposal are: 1) To screen for mutations that elicit a constitutive unfolded protein response (UPR), by identifying mutant animals that activate Green Fluorescent Protein reporter genes responsive to the UPR. 2) To stratify the mutants by the degree to which their viability or health are compromised by inactivation of either the translational or transcriptional components of UPR signaling. 3) To map and characterize mutants that display specific synthetic phenotypes with loss of PERK function and compare those with mutations that require IRE1 function.